Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers

One successful strategy for cancer chemoprevention is modulation of drug metabolizing enzymes, leading to a facilitated elimination of endogenous and environmental carcinogens. Inducers of phase 2 enzymes such as dithiolethiones inhibit tumorigenesis of environmental carcinogens in various animal models and modulate the metabolism of the carcinogen aflatoxin B ₁ in human clinical trials. Increasing lines of evidence show that the Keap1-Nrf2 complex is a key molecular target of chemopreventive phase 2 enzyme inducers. The transcription factor Nrf2 is a member of the basic leucine-zipper NF-E2 family and interacts with the antioxidant response element (ARE) in the promoter region of phase 2 detoxifying enzymes. A cytoplasmic actin-binding protein, Keap1, is an inhibitor of Nrf2 that sequesters it in the cytoplasm. Inducers dissociate this complex, allowing Nrf2 to translocate to the nucleus. Disruption of the nrf2 gene in mice leads to the loss of chemopreventive efficacy by inducers. This review focuses on (1) the role of Nrf2 in the regulation of phase 2 and antioxidative genes, (2) the molecular actions of dithiolethiones on the Keap1-Nrf2 pathway, and (3) the contribution of Nrf2-regulated gene families to the cytoprotective actions of dithiolethiones and other inducers. Rapidly accumulating data on this pathway is providing insight into the coordinated mammalian defense systems against electrophiles and oxidative stresses and the means by which it may be targeted by small molecules.